Inborn Error of Metabolism: PKU, Tay Sachs

Question 1

What is the usual inheritance pattern of inborn errors of metabolism?

Answer 1

Autosomal recessive (mostly), X-linked or mitochondrial

Question 2

Any given error of metabolism is quite rare. But as a group, what is their incidence?

Answer 2

1 in 2,500 live births

Question 3

Enzymopathies

Answer 3

Substance A turn in to substance B. An enzyme is needed fo rthis reaction to occur and the enzyme needs the cofactor in order to work. So when an enzyme isn’t present substance A builds up and there is no production of substance B. Substrate accumulation and prodcut deficiency.

Question 4

Many enzymes maintain normal state (normal substrate and product levels) with less
than ?% of full activity

Answer 4

10%

Question 5

An example of a ____________ is B vitaminsfor many enzymes.

Answer 5

cofactor

Question 6

Single gene defect may lead to loss of multiple enzyme activities.

Answer 6

• defect in a cofactor that is used by multiple enzymes
• if enzymes share a common subunit and when that subunit doesn’t function properly it effects them all.
• if the organelle in which they usually inhabit is missing or abnormal

Question 7

What is the most common etiology for PKU?

Answer 7

PAH (phenylalanine hydroxylase (enzyme)) deficiency
not enough enzyme

Question 8

What is the PAH (phenylalanine hydroxylase) cofactor?

Answer 8

tetrahydrobiopterin (BH4)
Defects in the gene that codes for this cofactor could lead to PKU

Autosomal Recessive

Question 9

Which gene encodes a chaperone for PAH (phenylalanine hydroxylase)?

Answer 9

DNAJC12
A rare cause of PKU

Aurtosomal Recessive

Question 10

Waht does a chaperone do?

Answer 10

facilitates the proper folding of a protein

Question 11

What are lysosomes?

Answer 11

The waste and recycling centers of the cell. The contain enzymes that digest large molecules.

Question 12

What are lysosome storage diseases?

Answer 12

When the lysosomal enzymes are defective waste materials build up inside the lysosome. This accumulation leads to symptoms.

Question 13

Lysosomal Storage Disorders are characterized by…

Answer 13

• accumulation of substrates inside the lysosome
• substrate accumulation and toxicity interferes with cell function leading to cell death

Question 14

What is the one uniform clinical feature of lysosome storage diseases?

Answer 14

PROGRESSION
this is becuase the disease is caused by substrate accumulation which takes time, so it is often not apparent at birth

Question 15

What is the inheritance pattern of lysosomal storage disorders?

Answer 15

• almost all are autosomal recessive
• 3 are X-linked: Fabry, Danon, and Hunter

Question 16

What is the combined incidence of all lysosomal storage disorders?

Answer 16

1 in 5,000 - 8,000

Question 17

Whcih lysosomal storage disorders are more common in the Ashkenazi Jewish population?

Answer 17

Gaucher and Tay Sach’s

Question 18

Lysosomal Storage Disorders often have brain involvement which causes progressive neurodegeneration.

Answer 18

There is also involvement of many organs.

Question 19

What are treatment options for lysosomal storage disorders?

Answer 19

• enzyme replacement therapy: unable to cross the blood brain barrier though
• stem cell transplantation: mus tbe done early and can have significant side effects

Question 20

Clinical course of Tay Sach’s

Answer 20

• normal until about 3-6 months
• progressive neurologic deterioration until death at 2-4 years old
• effects of neuronal death can be seen directly in the form of a cherry red spot in the retina

Question 21

Clinical manifestations of HEXA Tay Sach’s Disease

Answer 21

• later onset
• lower motor neuron dysfunction & ataxia
• 1/3 of patients develop psychosis
• intelligence and vision remain normal

Question 22

HEXA psuedodeficiency alleles

Answer 22

clinically benign
NO DISEASE
- individuals identified as pseudodeficient on screening are compound heterozygoteswith a pseudodeficiency allele and a common Tay-Sach’s variant on the other
- have about 20% functioning enzyme, which is sufficient to prevent GM2 ganglioside accumulation in the brain
- may be flagged as affceted on NBS incorreclty

Question 23

What is the carrier frequency for Tay Sachs among Ashkenazi Jews?

Answer 23

1 in 27